Cornelia de Lange Syndrome via the SMC3 Gene

Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation, hirsutism, and upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly. Craniofacial features include synophrys; arched eyebrows; long eyelashes; small, upturned nose; small, widely spaced teeth; and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement but often have facial features consistent with CdLS (Deardorff et al. GeneReview. 2011).

CdLS can be caused by variants in NIPBL, SMC1A, and SMC3. Variants in SMC3 account for <1% of CdLS (Deardorff et al. Am J Hum Genet 80:485–494, 2007). SMC3- related CdLS (OMIM #610759) is inherited in an autosomal dominant manner. SMC3 encodes structural maintenance of chromosomes protein 3, which is the human homolog of the yeast Smc3 gene, a core component of the cohesin complex forming a heterodimer with Smc1. The only reported variant in SMC3 is a single amino acid deletion (Deardorff et al. 2007; Revenkova et al. Hum Mol Genet 18:418-427, 2009).

This test is predicted to detect disease variants in <1% of individuals with clinical features of CdLS (Deardorff et al. 2007).

This test provides full coverage of all coding exons of the SMC3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).